Aggregation of a-synuclein is a characteristic event in Parkinsons disease and other synucleinopathies that show age-dependent progression. The aggregated forms of the protein are associated with the presence of Lewy bodies and other pathological events. It is not certain if Lewy bodies, or a-synuclein aggregation per se, are required for the disease process. What is clear is that a-synuclein can be a toxic protein in several cellular and animal models, although the molecular details of these events are not well understood. The aim of this project is to more clearly define what modifies a-synuclein aggregation and toxicity, and to try and understand why this is an age-related phenomenon. In the past reporting period, we have been actively involved in two projects related to the toxicity of a-synuclein using cultured cells as model systems. We have shown that native a-synuclein, prepared in a manner that does not generate oligomeric species that are competent for assembly, are not toxic to cells in culture. This supports previous data suggesting that aggregation of synuclein drives toxicity, although it refines our previous view in that it shows that not all aggregation is the same. Secondly, we have made progress towards a genomewide screen for modifiers of a-synuclein toxicity. We have developed inducible cell lines where a-synuclein expression can be switched off or on; these lines are currently undergoing testing to see if they can be used to then find additional genes that can limit these toxic effects.